Granulysin is an antimicrobial and tumoricidal molecule expressed in granul
es of CTL and NK cells. In this study, we show that granulysin damages cell
membranes based upon negative charge, disrupts the transmembrane potential
(Delta psi) in mitochondria, and causes release of cytochrome c. Granulysi
n-induced apoptosis is blocked in cells overexpressing Bcl-2. Despite the r
elease of cytochrome c, procaspase 9 is not processed. Nevertheless, activa
tion of caspase 3 is observed in granulysin-treated cells, suggesting that
granulysin activates a novel pathway of CTL- and NK cell-mediated death dis
tinct from granzyme- and death receptor-induced apoptosis.